Small conductance Ca2+-activated K+ channels (SK channels) are gated directly by Ca2+ ions. In many central neurons such as CA1 hippocampal neurons, SK channel activity underlies the medium component of the after hyperpolarization (mAHP) that follows an action potential, influencing the number of action potentials and the interspike interval during a burst, thereby regulating neuronal excitability. In addition, SK channels in CA1 neurons modulate the induction of synaptic plasticity and alter hippocampal-dependent learning. Blocking SK channels with apamin reduces the stimulus intensity that is required to induce NMDA receptor-dependent long-term potentiation at Schaffer collateral synapses, and reduces the number of training trials required for hippocampal dependent learning. To determine the distinct physiological roles for each SK channel subtype, homologous recombination has been used to generate transgenic mice for each of the three SK channel genes. Animals lacking SK2 channels are hyperexcitable, and completely lack the apamin-sensitive component of the AHP. Immunocytochemistry shows that plasma membrane SK2 channels are distributed to multiple subcellular compartments, the soma, dendritic shafts where they form discrete puncta, and dendritic spines. The driving hypothesis for this proposal is that in CA 1 neurons spatially and functionally discrete SK2 channel populations, embedded in distinct Ca2+ signaling microdomains, modulate the induction of synaptic plasticity and hippocampal-dependent learning. To test this hypothesis we will first measure the induction of synaptic plasticity at Shaffer collateral CA1 synapses, and hippocampal-dependent learning in wild type and SK transgenic mice. We will determine whether SK2 channels in dendritic spines are activated by an activity-dependent rise in spine Ca2+ flowing through NMDA receptors, thereby reducing the Ca2+ current through NMDA receptors, and whether dendritic SK2 channels modulate pairing-dependent, Hebbian forms of synaptic plasticity. We will determine the physiological consequences of the interactions between SK2 channels and seven candidate interacting proteins, and isolate and characterize intact SK2 channel microdomains. These studies will employ a novel repertoire of reagents and techniques to engender an integrated understanding of the roles SK2 channels play in fundamental aspects of neuronal excitability as well as synaptic plasticity and memory encoding.